Basophils and IgE contribute to mixed connective tissue disease development

Yasmine Lamri; Shamila Vibhushan; Emeline Pacreau; Erwan Boedec; Fanny Saidoune; Arnaud Mailleux; Bruno Crestani; Ulrich Blank; Marc Benhamou; Thomas Papo; Eric Daugas; Karim Sacré; Nicolas Charles

doi:10.1016/j.jaci.2020.12.622

Basophils and IgE contribute to mixed connective tissue disease development

J Allergy Clin Immunol. 2021 Apr;147(4):1478-1489.e11. doi: 10.1016/j.jaci.2020.12.622. Epub 2020 Dec 15.

Authors

Affiliations

¹ Université de Paris, Centre de Recherche sur l'Inflammation, INSERM UMR1149, CNRS ERL8252, Faculté de Médecine site Bichat, Paris, France; Université de Paris, Laboratoire d'Excellence Inflamex, Paris, France.
² Université de Paris, Laboratoire d'Excellence Inflamex, Paris, France; Université de Paris, INSERM UMR1152, Faculté de Médecine site Bichat, Paris, France.
³ Université de Paris, Laboratoire d'Excellence Inflamex, Paris, France; Université de Paris, INSERM UMR1152, Faculté de Médecine site Bichat, Paris, France; Department of Pulmonology, Hôpital Bichat, Assistance Publique-Hôpitaux de Paris, Université de Paris, Faculté de Médecine site Bichat, DHU FIRE, Paris, France.
⁴ Université de Paris, Centre de Recherche sur l'Inflammation, INSERM UMR1149, CNRS ERL8252, Faculté de Médecine site Bichat, Paris, France; Université de Paris, Laboratoire d'Excellence Inflamex, Paris, France; Department of Internal Medicine, Hôpital Bichat, Assistance Publique-Hôpitaux de Paris, Université de Paris, Faculté de Médecine site Bichat, DHU FIRE, Paris, France.
⁵ Université de Paris, Centre de Recherche sur l'Inflammation, INSERM UMR1149, CNRS ERL8252, Faculté de Médecine site Bichat, Paris, France; Université de Paris, Laboratoire d'Excellence Inflamex, Paris, France; Department of Nephrology, Hôpital Bichat, Assistance Publique-Hôpitaux de Paris, Université de Paris, Faculté de Médecine site Bichat, DHU FIRE, Paris, France.
⁶ Université de Paris, Centre de Recherche sur l'Inflammation, INSERM UMR1149, CNRS ERL8252, Faculté de Médecine site Bichat, Paris, France; Université de Paris, Laboratoire d'Excellence Inflamex, Paris, France. Electronic address: nicolas.charles@inserm.fr.

PMID: 33338538
DOI: 10.1016/j.jaci.2020.12.622

Abstract

Background: Mixed connective tissue disease (MCTD) is a rare and complex autoimmune disease that presents mixed features with other connective tissue diseases, such as systemic lupus erythematosus, systemic sclerosis, and myositis. It is characterized by high levels of anti-U1 small nuclear ribonucleoprotein 70k autoantibodies and a high incidence of life-threatening pulmonary involvement. The pathophysiology of MCTD is not well understood, and no specific treatment is yet available for the patients. Basophils and IgE play a role in the development of systemic lupus erythematosus and thus represent new therapeutic targets for systemic lupus erythematosus and other diseases involving basophils and IgE in their pathogenesis.

Objective: We sought to investigate the role of basophils and IgE in the pathophysiology of MCTD.

Methods: Basophil activation status and the presence of autoreactive IgE were assessed in peripheral blood of a cohort of patients with MCTD and in an MCTD-like mouse model. Basophil depletion and IgE-deficient animals were used to investigate the contribution of basophils and IgE in the lung pathology development of this mouse model.

Results: Patients with MCTD have a peripheral basopenia and activated blood basophils overexpressing C-C chemokine receptor 3. Autoreactive IgE raised against the main MCTD autoantigen U1 small nuclear ribonucleoprotein 70k were found in nearly 80% of the patients from the cohort. Basophil activation and IgE anti-U1 small nuclear ribonucleoprotein 70k were also observed in the MCTD-like mouse model along with basophil accumulation in lymph nodes and lungs. Basophil depletion dampened lung pathology, and IgE deficiency prevented its development.

Conclusions: Basophils and IgE contribute to MCTD pathophysiology and represent new candidate therapeutic targets for patients with MCTD.

Keywords: Basophil; IgE; MCTD-like mouse model; interstitial lung disease; mixed connective tissue disease; pathophysiology.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adult
Animals
Autoantibodies / immunology*
Basophils / immunology*
Female
Humans
Immunoglobulin E / immunology*
Lung / immunology
Lung / pathology
Lymph Nodes / immunology
Male
Mice, Transgenic
Middle Aged
Mixed Connective Tissue Disease / immunology*
Mixed Connective Tissue Disease / pathology
Ribonucleoprotein, U1 Small Nuclear / immunology*

Substances

Autoantibodies
Ribonucleoprotein, U1 Small Nuclear
SNRNP70 protein, human
Immunoglobulin E